Although this would limit time spent responding to posts and limit the tongue lashings that Prof G often gets, we felt that it does give you an oppertunity to ask questions. In addition they give us ideas for posts and your comments are often some of the most enligthening features, so we think it is best to keep these.

We accept that your comments are not always going to be positive, but it helps if the comments are constructive when being negative.

"The Google trend data on CCSVI continues to show a downward trend. The majority of hits are still from Canada, Italy and Serbia; a very interesting regional social phenomenon."

"When the dust settles on CCSVI it will be worth a detailed analysis to see if we can learn any lessons to prevent this from happening again."

"Too much money, energy and most importantly human life has been wasted on this issue. Not to mention the impact it has had on the relationships between patients, patient advocates and healthcare professionals."

38 patients have died (21%); most of the deaths have occurred within approximately 2 months after PML diagnosis

143 patients are alive (79%), it is too early to draw conclusions about the outcomes of patients who develop PML while on natalizumab treatment.

The following is the risk profiling algorithm with updated risks:

"It is clear that Natalizumab is associated with a risk of getting PML that varies depending on JC viral status, previous exposure to other immunosuppressive drugs and duration of treatment. Knowing these risks will allow you and your neurologist to make an informed decision on what to do with your treatment."

"In my opinion, a defined risk is better than an undefined risk."

CoI: Multiple, please note that all the data in this post has been supplied by Biogen-Idec as part of their "monthly natalizumab safety update and PML risk stratification programme".

Within the vertebrate nervous system, myelination is required for the normal function of neurons (nerves) by facilitating the rapid conduction of action potentials (nerve impulses) along axons. Oligodendrocytes (myelin-forming cells) are glial cells which myelinate axons in the central nervous system. Disruption of myelination and remyelination failure occur in diseases such as multiple sclerosis.

Despite the importance of myelination, the molecular basis of oligodendrocyte differentiation (generation of oligodendrocytes from more immature cells) and myelination are still poorly understood. To understand the molecular mechanisms which regulate oligodendrocyte differentiation and myelination, novel genes were identified using a microarray analysis (this looks for the genetic messages that are switched on to make proteins that are required for the function of the cells being analysed) . The analysis used oligodendrocyte lineage cells isolated from transgenic zebrafish expressing fluorescent (glow-in-the dark) proteins in the oligodendrocyte (myelin-forming cell) lineage cells. Seven genes ("I think it is not worth talking about these yet as it is too early")not previously known to be involved in oligodendrocyte differentiation were identified, and their expression during oligodendrocyte development was validated.

Zebrafish are model organisms that the scientific community use to study genes and development (How we go from a fertilised egg to make the adult). They have young that are transparent and so by shining ulta violet light onto the genetically engineered-fish, then you can see when the flourescent (glow-in the dark) proteins indicating that myelination (in the case above) is occurring. You can then hunt to see which proteins are switched on using a process called micro array analysis, which looks for the messages that tell proteins to be produced.

This study has identified new molecules in addition to those known to be involved in the production of myelin. The more boffins know about this, the more likely that we will be able to develop drugs to help stimulate remyelination. So as you can see not all research involves mice. However this information is some way off leading to treatments and we need to ensure that these new targets are involved in myelination and importantly remyelination by human cells.

It's that time of year and soon January 2012 will be upon us. To help you rembember our MS Research Day on the 28th January, in Westminister Central London. You are all invited and it's free...now that's what I call a Christmas present. As treat I am doing Calender Mouse and will be shedding my usual white coat to put on some new outfits for our advent calendar that starts tomorrow.

Please remember to register your interests for the Research Day, You can do this if you Click Here.

Can't wait to open the first window and we will give you hints of what's in store so remember to register

BACKGROUND AND PURPOSE: It is well known that patients with MS tend to have abnormal iron deposition in and around the MS plaques in the brain. In this study, we quantify iron content in patients with MS and healthy volunteers.

MATERIALS AND METHODS: Fifty-two patients with MS were recruited to assess abnormal iron content in brain structures involved in movement. One hundred twenty-two healthy subjects were recruited to establish a baseline of normal iron content in deep grey matter structures.

RESULTS: A clear separation between iron content in healthy subjects versus patients with MS was seen. For healthy subjects 13% and for patients with MS 65% showed an iron-weighting factor greater than three standard deviations from the normal mean (P < .05). Standard deviation is a measure of variability around a mean (average. middle point). 1.96 standard deviations would be expected contain 95% of the results and >3 standard deviations only less than 0.5% of results would be expected to occur at this level if it occured by chance. So the chance result would occur in 1 in a thousand times you do the experiment but would occur 650 times in a thousand (65%) so these results are unlikely to be a chance result. The results for those patients younger than 40 years are even more impressive. In these cases, only 1% of healthy subjects and 67% of patients with RRMS showed abnormally high iron content.

CONCLUSIONS: Iron-weighting factors in the brain appeared to be abnormal in roughly two-thirds of patients with MS

Although CSSVI'ers may take heart from this, as Dr. Z from Italy theorized that malformed blood vessels cause increased deposition of iron in the brain, which in turn triggers the problems of MS. Altered iron levels and MS have been reported for decades and iron deposits occur in other neurological diseases and EAE in animals that have not been associated with CSSVI. Yet further examples of repetative research no doubt triggered by the Dr. Z. studies.

PATIENTS: 39 MS'ers with clinically defined benign MS and an age-matched group of 40 MS'ers with early RRMS.

RESULTS: The mean (SD) annualized brain atrophy rate in MS'ers with benign MS (-0.16% [0.51%]) was lower than that in patients with early MS (-0.46% [0.72%]) (P = .02). The difference remained significant after controlling for age, sex, and treatment (P = .04).

CONCLUSIONS: Serial magnetic resonance imaging revealed a low 2-year rate of brain atrophy in MS'ers with clinically benign MS, suggesting a less prominent degenerative component in its pathogenesis than in patients with typical early MS. Identification of patients with a low rate of brain atrophy may indicate a benign course.

"This MRI study does suggest that MS'ers with 'benign MS' behave differently to MS'ers with RRMS. The downside is that benign MS'ers still had brain atrophy. Is this benign disease? I don't think so."

Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.

Be between the ages of 18 and 58, inclusive, at the time of informed consent.

SPMS defined as relapsing-remitting disease followed by progression of disability independent of or not explained by MS relapses for at least 2 years.

EDSS score of 3.0 to 6.5, inclusive.

MS Severity Score (MSSS) of 4 or higher.

Documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide.

Major Exclusion Criteria:

RRMS or primary progressive MS as defined by the revised McDonald Committee criteria.

Clinical relapse (within 3 months) prior to randomization.

T25FW test of >30 seconds during the screening.

Any value below the lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils.

Considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines, or due to prior immunosuppressive or immunomodulating treatment.

Subjects for whom MRI is contraindicated (i.e., have pacemakers or other contraindicated implanted metal devices, are allergic to gadolinium, or have claustrophobia that cannot be medically managed).

History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease that would preclude participation in a clinical study.

History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).

Known history of or positive test result for Human Immunodeficiency Virus (HIV).

Treatment with IV or oral corticosteroids, intravenous immunoglobulin (IVIg), or plasmapheresis for treatment of MS within the 3 months prior to randomization.

Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks prior to randomization.

Treatment with 4-aminopyridine within 30 days prior to randomization, unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study.

This short YouTube video from Biogen-Idec and Elan explains how the drug works. Some of you may find it helpful.

"A Big Pharma Trial in SPMS; I would rate the chances of this study being positive as being >80%. Why? Because the drug is very effective at switching of relapses and MRI activity, i.e. it is a powerful anti-inflammatory drug and inflammation still plays a part in SPMS."

Sunday, 27 November 2011

"I don't find this result surprising given the current reputational issues Big Pharma have with the general public.However, I disagree with these results. If it wasn't for Big Pharma we wouldn't have DMTs for MS or the exciting pipeline that currently exists."

"MS'ers may be surprised but there are currently two PPMS and one SPMS trial recruiting sponsored by Big Pharma. The anti-Lingo trial that is targeting remyelination is also a Big Pharma project. All these have been profiled on this blog in the recent past."

"What is worrying however is the bad publicity "big money" brings to the field."

"It is also becoming increasingly difficult to get investigator trials sponsored, for example funding for a recent vitamin D trial was turned down in the UK. We are not sure why as the trial was well designed, the case for vitamin D is compelling and the study was powered to be definitive. May be next time?"

"We are about to submit a grant to test an anti-EBV drug in MS. Again the case is compelling for this trial. Let's hope the reviewers' and funders' think the same."

"I wonder if Danone and/or Nestle would be interested in funding a probiotic trial in MS? Please complete the new poll to let us know. You never know your response may be the beginning of a powerful lobby."

The Red Queen Effect, is a term taken from the Red Queen's race in Lewis Carroll's Through the Looking-Glass. The Red Queen said, "It takes all the running you can do, to keep in the same place." The marketing departments ...

Saturday, 26 November 2011

Do you think probiotics should be tested as a potential disease-modifying therapy (DMT) in MS?

If you are using a mobile blogger to view this post or email alerts please log-on via the web to complete the poll.

What are probiotics?

Probiotics are live microorganisms thought to be beneficial to the host organism. The currently adopted definition by FAO/WHO, probiotics are: "Live microorganisms which when administered in adequate amounts confer a health benefit on the host".

Lactic acid bacteria (LAB) and bifidobacteria are the most common types of microbes used as probiotics; but certain yeasts and bacilli may also be helpful. Probiotics are commonly consumed as part of fermented foods with specially added active live cultures; such as in yogurt, soy yogurt, or as dietary supplements.

BACKGROUND: Certain intestinal microflora are thought to regulate the systemic immune response. Lactic acid bacteria are one of the most studied bacteria in terms of their beneficial effects on health and autoimmune diseases; one of which is MS. They investigated whether the lactic acid bacterium Pediococcus acidilactici, which comprises human commensal bacteria, has beneficial effects on experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

CONCLUSIONS: An orally administered single strain of P. acidilactici R037 ameliorates EAE by inducing regulatory cells. Their findings indicate the therapeutic potential of the oral administration of R037 for treating MS.

"Interesting study; I wonder if the same effects will be seen in humans. Can you imagine the nutriceutical industry getting involved with this? Danone or Nestle sponsor lactobacillus trial in MS!!"

METHODS: Two patients were evaluated with ON refractory to steroid therapy and poor visual acuity; they were tested for NMO-IgG antibodies.

RESULTS: Brain magnetic resonance imaging was normal in both patients. The serum and cerebrospinal fluid were positive for NMO-IgG antibodies. Magnetic resonance imaging of the cervical and thoracic spine revealed lesions longer than three vertebral segments (3 back bones) and the diagnosis of NMO was confirmed. Treatment with plasma exchange and immunosuppressive therapy resulted in marked improvement of visual acuity. This improvement was sustained.

Spinal cord lesion in NMO

CONCLUSIONS.: The testing for NMO-IgG antibodies is important for distinguishing ON in NMO from multiple sclerosis in cases of ON refractory to steroid treatment. These cases suggest that testing for NMO-IgG antibodies should be performed in comparative trials on a larger series.

Although this study examines too few MSers this is a useful point to consider. Optic-spinal MS (affects the optic nerve and spinal cord with little involvement in the brain): this is a relatively rare form of MS that is most common in Asia and Japan. The majority of these cases now have a specific antibody (NMO-Ig) that can be detected in their blood that labels them as having a disease that we call neuromyelitis optica or NMO. This is an autoimmune disease targeting astrocytes – star-shaped glial cells in the brain and spinal cord. Anti-aquaporin-4 antibodies (NMO-Ig), which are directed against this astrocytic water channel, are involved in the disease pathogenesis and used as diagnostic markers.

Friday, 25 November 2011

The objective of the study was to treat fatigue in MS'ers by a neurocognitive rehabilitation program aimed at improving motor planning by using motor imagery (MI). 20 MS'ers complaining of fatigue were treated for 5 weeks with exercises of neurocognitive rehabilitation twice a week. MS'ers were evaluated by Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS), MSQoL54, Expanded Disability Status Scale (EDSS), and MS Functional Composite (MSFC).

After treatment, a decrease in fatigue was detected with both FSS (P = 0.0001) and MFIS (P = 0.0001). MSFC (P = 0.035) and MSQoL54 (P = 0.002) scores improved compared to baseline. At six-month followup, the improvement was confirmed for fatigue (FSS, P = 0.0001; MFIS P = 0.01) and for the physical subscale of MSQoL54 (P = 0.049). No differences in disability scales were found. These results show that neurocognitive rehabilitation, based on MI, could be a strategy to treat fatigue in MS patients.

"This study is too small to draw any conclusions, but it does suggest that fatigue may respond to some interventions. I don't have any experience with motor imagery. Do any of you?"

The mammalian nervous system is characterized by myelination, a fundamental biological process that protects the nerve processes of axons and facilitates the transmission of electrical pulses.

Damage to myelin is considered the major problem in MS. Currently, therapeutic interventions are focused on protecting myelin integrity and promoting myelin repair. These efforts need to be accompanied by an effective imaging tool that correlates the disease progression with the extent of myelination.

Purpose: Neurogenic detrusor overactivity (NDO. The muscle controlling bladder contraction is over active = urinary incontinence) is common in patients who suffer from multiple sclerosis (MS). When the usual pharmacological treatment fails, botulinum toxin type A (BTX-A=Botox) injections can be proposed. The safety and efficacy of this treatment are already well known, but only a few studies focus on its use in patients with MS.

Materials and Methods: Seventy-one patients with MS underwent their first BTX-A injection for refractory (doesn't respond to therapy) NDO. They had bladder function assessed before and three months after injection. The patients were divided in three groups according to treatment efficacy: full success (total urinary continence, no overactive detrusor), improvement, or total failure (urge incontinence and overactive detrusor = when you've gotta, you've gotta go).

BoTox Injection Sites

Results: 77% of the patients had clinical improvement or full success of the treatment with a reduction of their urgency and incontinence. Significant urodynamic improvement after treatment was shown on different parameters: volume at first involuntary bladder contraction (p = 0.0000001), maximum vladder capacity (p = 0.0035), maximum detrusor pressure (p = 0.0000001). 46% of the patients were in the ″ full success ″ group. 31% of the patients had a partial improvement. 23% of the patients had no efficacy of the treatment. Duration of MS was a predictive factor of treatment failure (p = 0.015).

Conclusions: Despite that a full success was obtained in 46% of the cases, BTX-A injection therapy failed to treat refractory NDO in 23% of patients suffering from MS. Duration of the disease was a predictive factor for an inefficient treatment. The injection therapy should be considered as soon as oral anti-cholinergic (inhibit acetyl choline that is a nerve transmitter chemical) drugs fail to reduce NDO.

More confirmatory evidence for the value of Botox...its not just about fixing foreheads but it can be a valuble medicine. Please leave a look at previous posts

Thursday, 24 November 2011

Following the bombshell dropped by G about shutting the blog down, at your suggestion (see comments) that it's time to give up EAE and become a RockGod .....................Again. I have dumped the lab coat and put on my outfit for a new evening job,....no it's not a gimp suit. I bet you never guessed I play bass with Kiss under all that make-up. MouseDoctor II is going down the supermarket packing shelves.

However let's not be glum, today is a special day, it is the forth thursday in November. So many of our readers (in America) get a few days thanksgiving holiday. It's not about giving presents, but time to nosh on a turkey and celebrate a good harvest with family and friends. They've been doing this since 1621. However, we Brits like to give presents on our long (OK the Scots don't get one as theirs is in New Year) National holiday in December, so I give you details from a recent email conversation with the boss.

MouseDoc: "So when and why are you going to shut it down?"

Prof G: "I was having one of those days when I made the comment, but with the amazing response we've had, we've just got to keep it going!"

So you're going to have to put up with Prof & Team G for more of the "Same Old, Same Old". (you can groan if you think its not good news)

After G gets over another strenous week, we will digest your suggestions (thank you) and have a chat about how we juggle things.

So Happy Thanksgiving from Dr & Ms. Mouse (My American Other half) enjoy your Turkey (Nut Loaf for the Veggies) and see you over the weekend or next week!

BACKGROUND:Myelin/oligodendrocyte glycoprotein (MOG) is a putative autoantigen in multiple sclerosis (MS). Establishing the pathological relevance and validity of anti-MOG antibodies as biomarkers has yielded conflicting reports mainly due to different MOG isoforms used in different studies. Because epitope specificity may be a key factor determining anti-MOG reactivity we aimed at identifying a priori immunodominant MOG epitopes by monoclonal antibodies (mAbs) and at assessing clinical relevance of these epitopes in MS.

CONCLUSIONS:Thus high-titre reactivity likely represents high-affinity antibodies against pathologically relevant MOG epitopes, that are only present in a small proportion of patients with MS.

"MOG is one of the few myelin targets that is available to attack by antibodies. In animals immune responses to this protein can drive relapsing neurological attacks and antibodies can induce demyelination. This study suggests that such antibodies present in MS could contribute to problems. However, that these antibodies are not ubiquitous (common to every one) suggests that autoimmunity to this protein cannot fully account for the problems of MS. However it should be said that other studies have reported a higher incidence of anti-myelin antibodies. It is feasible that different people will react to different myelin proteins, as is known and is likely to occur. However, it may suggest such that antibodies can be produced as a consequence of other damaging entities that could trigger this autoimmunity

Do I think that antibodies that react with targets within the CNS are a problem in MS. Well yes I do and I'm pretty sure of that because we can take antibodies for MSers and inject them into animals and see undesirable effects.

PML Risk Infographic

Holistic Management of MS ver. 7.0

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General Disclaimer: Please note that the opinions expressed here are those of the individual bloggers and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry, Queen Mary University of London or Barts Health NHS Trust.

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